Cellular and Molecular Life Sciences

, Volume 72, Issue 6, pp 1185–1196 | Cite as

Prion strains are differentially released through the exosomal pathway

  • Zaira E. Arellano-Anaya
  • Alvina Huor
  • Pascal Leblanc
  • Sylvain Lehmann
  • Monique Provansal
  • Graça Raposo
  • Olivier Andréoletti
  • Didier Vilette
Research Article

Abstract

Cell-to-cell transfer of prions is a crucial step in the spreading of prion infection through infected tissue. At the cellular level, several distinct pathways including direct cell–cell contacts and release of various types of infectious extracellular vesicles have been described that may potentially lead to infection of naïve cells. The relative contribution of these pathways and whether they may vary depending on the prion strain and/or on the infected cell type are not yet known. In this study we used a single cell type (RK13) infected with three different prion strains. We showed that in each case, most of the extracellular prions resulted from active cell secretion through the exosomal pathway. Further, quantitative analysis of secreted infectivity indicated that the proportion of prions eventually secreted was dramatically dependent on the prion strain. Our data also highlight that infectious exosomes secreted from cultured cells might represent a biologically pertinent material for spiking experiments. Also discussed is the appealing possibility that abnormal PrP from different prion strains may differentially interact with the cellular machinery to promote secretion.

Keywords

Prion release Cell models Exosome Extracellular vesicle Prion spiking TSE agent 

References

  1. 1.
    Collinge J (2001) Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24:519–550CrossRefPubMedGoogle Scholar
  2. 2.
    Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Castilla J, Saa P, Hetz C, Soto C (2005) In vitro generation of infectious scrapie prions. Cell 121:195–206CrossRefPubMedGoogle Scholar
  4. 4.
    Beringue V, Vilotte JL, Laude H (2008) Prion agent diversity and species barrier. Vet Res 39:47CrossRefPubMedGoogle Scholar
  5. 5.
    Mabbott NA, MacPherson GG (2006) Prions and their lethal journey to the brain. Nat Rev Microbiol 4:201–211CrossRefPubMedGoogle Scholar
  6. 6.
    Vilette D (2008) Cell models of prion infection. Vet Res 39:10CrossRefPubMedGoogle Scholar
  7. 7.
    Kanu N, Imokawa Y, Drechsel DN, Williamson RA, Birkett CR et al (2002) Transfer of scrapie prion infectivity by cell contact in culture. Curr Biol 12:523–530CrossRefPubMedGoogle Scholar
  8. 8.
    Paquet S, Langevin C, Chapuis J, Jackson GS, Laude H et al (2007) Efficient dissemination of prions through preferential transmission to nearby cells. J Gen Virol 88:706–713CrossRefPubMedGoogle Scholar
  9. 9.
    Langevin C, Gousset K, Costanzo M, Richard-Le Goff O, Zurzolo C (2010) Characterization of the role of dendritic cells in prion transfer to primary neurons. Biochem J 431:189–198CrossRefPubMedGoogle Scholar
  10. 10.
    Gousset K, Schiff E, Langevin C, Marijanovic Z, Caputo A et al (2009) Prions hijack tunnelling nanotubes for intercellular spread. Nat Cell Biol 11:328–336CrossRefPubMedGoogle Scholar
  11. 11.
    Mattei V, Barenco MG, Tasciotti V, Garofalo T, Longo A et al (2009) Paracrine diffusion of PrP(C) and propagation of prion infectivity by plasma membrane-derived microvesicles. PLoS ONE 4:e5057CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Alais S, Simoes S, Baas D, Lehmann S, Raposo G et al (2008) Mouse neuroblastoma cells release prion infectivity associated with exosomal vesicles. Biol Cell 100:603–615CrossRefPubMedGoogle Scholar
  13. 13.
    Fevrier B, Vilette D, Archer F, Loew D, Faigle W et al (2004) Cells release prions in association with exosomes. Proc Natl Acad Sci U S A 101:9683–9688CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Vella LJ, Sharples RA, Lawson VA, Masters CL, Cappai R et al (2007) Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J Pathol 211:582–590CrossRefPubMedGoogle Scholar
  15. 15.
    Bellingham SA, Guo BB, Coleman BM, Hill AF (2012) Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front Physiol 3:124CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Schneider A, Simons M (2013) Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res 352:33–47CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Vingtdeux V, Sergeant N, Buee L (2012) Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front Physiol 3:229CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Arellano-Anaya ZE, Savistchenko J, Mathey J, Huor A, Lacroux C et al (2011) A simple, versatile and sensitive cell-based assay for prions from various species. PLoS ONE 6:e20563CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Vilette D, Andreoletti O, Archer F, Madelaine MF, Vilotte JL et al (2001) Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proc Natl Acad Sci USA 98:4055–4059CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Courageot MP, Daude N, Nonno R, Paquet S, Di Bari MA et al (2008) A cell line infectible by prion strains from different species. J Gen Virol 89:341–347CrossRefPubMedGoogle Scholar
  21. 21.
    Vilotte JL, Soulier S, Essalmani R, Stinnakre MG, Vaiman D et al (2001) Markedly increased susceptibility to natural sheep scrapie of transgenic mice expressing ovine PrP. J Virol 75:5977–5984CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Le Dur A, Beringue V, Andreoletti O, Reine F, Lai TL et al (2005) A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes. Proc Natl Acad Sci USA 102:16031–16036CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Nonno R, Di Bari MA, Cardone F, Vaccari G, Fazzi P et al (2006) Efficient transmission and characterization of Creutzfeldt–Jakob disease strains in bank voles. PLoS Pathog 2:e12CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Piening N, Nonno R, Di Bari M, Walter S, Windl O et al (2006) Conversion efficiency of bank vole prion protein in vitro is determined by residues 155 and 170, but does not correlate with the high susceptibility of bank voles to sheep scrapie in vivo. J Biol Chem 281:9373–9384CrossRefPubMedGoogle Scholar
  25. 25.
    Feraudet C, Morel N, Simon S, Volland H, Frobert Y et al (2005) Screening of 145 anti-PrP monoclonal antibodies for their capacity to inhibit PrPSc replication in infected cells. J Biol Chem 280:11247–11258CrossRefPubMedGoogle Scholar
  26. 26.
    Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Curr Protoc Cell Biol, Chapter 3: Unit 3 22Google Scholar
  27. 27.
    van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R et al (2001) Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology 121:337–349CrossRefPubMedGoogle Scholar
  28. 28.
    Coleman BM, Hanssen E, Lawson VA, Hill AF (2012) Prion-infected cells regulate the release of exosomes with distinct ultrastructural features. FASEB J 26:4160–4173CrossRefPubMedGoogle Scholar
  29. 29.
    Castro-Seoane R, Hummerich H, Sweeting T, Tattum MH, Linehan JM et al (2012) Plasmacytoid dendritic cells sequester high prion titres at early stages of prion infection. PLoS Pathog 8:e1002538CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Leblanc P, Alais S, Porto-Carreiro I, Lehmann S, Grassi J et al (2006) Retrovirus infection strongly enhances scrapie infectivity release in cell culture. EMBO J 25:2674–2685CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE et al (2006) Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol 172:923–935CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Gill ON, Spencer Y, Richard-Loendt A, Kelly C, Dabaghian R et al (2013) Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ 347:f5675CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Edgeworth JA, Farmer M, Sicilia A, Tavares P, Beck J et al (2011) Detection of prion infection in variant Creutzfeldt–Jakob disease: a blood-based assay. Lancet 377:487–493CrossRefPubMedGoogle Scholar
  34. 34.
    Foster PR (2008) Selection of spiking materials for studies on the clearance of agents of transmissible spongiform encephalopathy during plasma fractionation. Biologicals 36:142–143CrossRefPubMedGoogle Scholar
  35. 35.
    Kujala P, Raymond CR, Romeijn M, Godsave SF, van Kasteren SI et al (2011) Prion uptake in the gut: identification of the first uptake and replication sites. PLoS Pathog 7:e1002449CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Gough KC, Maddison BC (2010) Prion transmission: prion excretion and occurrence in the environment. Prion 4:275–282CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Dassanayake RP, Schneider DA, Truscott TC, Young AJ, Zhuang D et al (2011) Classical scrapie prions in ovine blood are associated with B lymphocytes and platelet-rich plasma. BMC Vet Res 7:75CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Douet JY, Zafar S, Perret-Liaudet A, Lacroux C, Lugan S et al (2014) Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt–Jakob disease. Emerg Infect Dis 20:114–117CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Houston F, Foster JD, Chong A, Hunter N, Bostock CJ (2000) Transmission of BSE by blood transfusion in sheep. Lancet 356:999–1000CrossRefPubMedGoogle Scholar
  40. 40.
    Mathiason CK, Hayes-Klug J, Hays SA, Powers J, Osborn DA et al (2010) B cells and platelets harbor prion infectivity in the blood of deer infected with chronic wasting disease. J Virol 84:5097–5107CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R et al (2007) Exosomes with immune modulatory features are present in human breast milk. J Immunol 179:1969–1978CrossRefPubMedGoogle Scholar
  42. 42.
    Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17:879–887CrossRefPubMedGoogle Scholar
  43. 43.
    Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci USA 101:13368–13373CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Brown P, Rohwer RG, Dunstan BC, MacAuley C, Gajdusek DC et al (1998) The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion 38:810–816CrossRefPubMedGoogle Scholar
  45. 45.
    Cervenakova L, Yakovleva O, McKenzie C, Kolchinsky S, McShane L et al (2003) Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy. Transfusion 43:1687–1694CrossRefPubMedGoogle Scholar
  46. 46.
    Gregori L, McCombie N, Palmer D, Birch P, Sowemimo-Coker SO et al (2004) Effectiveness of leucoreduction for removal of infectivity of transmissible spongiform encephalopathies from blood. Lancet 364:529–531CrossRefPubMedGoogle Scholar
  47. 47.
    Andreoletti O, Litaise C, Simmons H, Corbiere F, Lugan S et al (2012) Highly efficient prion transmission by blood transfusion. PLoS Pathog 8:e1002782CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    McCutcheon S, Alejo Blanco AR, Houston EF, de Wolf C, Tan BC et al (2011) All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD. PLoS ONE 6:e23169CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Vlassov AV, Magdaleno S, Setterquist R, Conrad R (2012) Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 1820:940–948CrossRefPubMedGoogle Scholar
  50. 50.
    Bellingham SA, Coleman BM, Hill AF (2012) Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res 40:10937–10949CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Klohn PC, Stoltze L, Flechsig E, Enari M, Weissmann C (2003) A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc Natl Acad Sci USA 100:11666–11671CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Bobrie A, Colombo M, Raposo G, Thery C (2011) Exosome secretion : molecular mechanisms and roles in immune responses. Traffic 12(12):1659–1668CrossRefPubMedGoogle Scholar
  53. 53.
    Lakkaraju A, Rodriguez-Boulan E (2008) Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol 18:199–209CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Futter CE, Collinson LM, Backer JM, Hopkins CR (2001) Human VPS34 is required for internal vesicle formation within multivesicular endosomes. J Cell Biol 155:1251–1264CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Pan BT, Teng K, Wu C, Adam M, Johnstone RM (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101:942–948CrossRefPubMedGoogle Scholar
  56. 56.
    Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV et al (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172CrossRefPubMedGoogle Scholar
  57. 57.
    Michelet X, Djeddi A, Legouis R (2010) Developmental and cellular functions of the ESCRT machinery in pluricellular organisms. Biol Cell 102:191–202CrossRefPubMedGoogle Scholar
  58. 58.
    Stuffers S, Sem Wegner C, Stenmark H, Brech A (2009) Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic 10:925–937CrossRefPubMedGoogle Scholar
  59. 59.
    Theos AC, Truschel ST, Tenza D, Hurbain I, Harper DC et al (2006) A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev Cell 10:343–354CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D et al (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247CrossRefPubMedGoogle Scholar
  61. 61.
    van Niel G, Charrin S, Simoes S, Romao M, Rochin L et al (2011) The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev Cell 21:708–721CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Savistchenko J, Arellano-Anaya ZE, Andreoletti O, Vilette D (2011) Mammalian prions: tracking the infectious entities. Prion 5:84–87CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Arellano Anaya ZE, Savistchenko J, Massonneau V, Lacroux C, Andreoletti O et al (2011) Recovery of small infectious PrPres aggregates from prion-infected cultured cells. J Biol Chem 86:8141–8148CrossRefGoogle Scholar
  64. 64.
    Laferriere F, Tixador P, Moudjou M, Chapuis J, Sibille P et al (2013) Quaternary structure of pathological prion protein as a determining factor of strain-specific prion replication dynamics. PLoS Pathog 9:e1003702CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Tixador P, Herzog L, Reine F, Jaumain E, Chapuis J et al (2010) The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLoS Pathog 6:e1000859CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Zaira E. Arellano-Anaya
    • 1
    • 2
  • Alvina Huor
    • 1
    • 2
  • Pascal Leblanc
    • 3
  • Sylvain Lehmann
    • 4
    • 5
  • Monique Provansal
    • 4
    • 5
  • Graça Raposo
    • 6
  • Olivier Andréoletti
    • 1
    • 2
  • Didier Vilette
    • 1
    • 2
  1. 1.INRA, UMR 1225, IHAPToulouseFrance
  2. 2.Université de Toulouse, INP, ENVT, UMR 1225, IHAPToulouseFrance
  3. 3.Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Equipe Différenciation Neuromusculaire, Ecole Normale Supérieure-LyonCNRS, UMR 5239Lyon Cedex 07France
  4. 4.Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Physiopathologie, Diagnostic et Thérapie Cellulaire des Affections Neurodégénératives, Institut National de la Santé et de la Recherche Médicale Université Montpellier 1 U1040 Centre Hospitalo-Universitaire de Montpellier, Université Montpellier 1MontpellierFrance
  5. 5.Institut de Génétique Humaine, Centre National de la Recherche Scientifique, UPR 1142MontpellierFrance
  6. 6.Institut Curie, UMR 144, CNRS, Structure and Membrane Compartments, Cell and Tissue Imaging Facility (PICT-IBiSA)Paris Cedex 05France

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